Genetic Studies on Multiple Consanguineous Families Segregating Diverse Phenotypes of Microphthalmia Identified Novel and Recurrent Mutations.

Introduction: Anophthalmia/microphthalmia (A/M) and anterior segment dysgenesis (ASD) are severe ocular anomalies impacting eye morphology, occurring in 30 per 100,000 live births. Genetic research has identified over 30 genes linked to A/M anomalies, with their products mainly involved in eye organogenesis.

Aims and objectives: This study examined two consanguineous A/M families to identify disease-associated pathogenic mutations and predict their functional impact.

Methodology: Patients were clinically examined using A-scan and ophthalmic ultrasonography. Whole exome sequencing (WES) identified candidate pathogenic variants validated through Sanger sequencing. Computational analyses assessed the impact of these mutations on protein structure and function.

Results: The clinical diagnosis of family A revealed microphthalmia with ASD, while family B presented with an A/M phenotype. Exome analysis of family A identified a novel missense variant, NM_012293:c.A3742G [p.(Arg1248Gly)], in the peroxidasin (PXDN) gene (ClinVar ID: VCV001333267.1). At the cellular level, PXDN is involved in establishing sulfilimine bonds in collagen IV, a component of the basement membrane, suggesting that ocular defects may result from impaired integrity of the basement membrane in the developing eye. In contrast, Family B exhibited a nonsense variant NM _012186:c.720C>A (p.- Cys240*) in the FOXE3 gene. This variant has been previously reported in other South Asian populations, suggesting a founder effect in subcontinent populations. Structural modeling and simulation analysis of mutant proteins revealed altered properties, thus corroborating the pathogenicity of the identified mutation.

Conclusion: Our findings may contribute to the elucidation of genotype-phenotype correlations, potentially facilitating the molecular diagnosis of microphthalmia and ASD.